Many modern medical procedures require that synthetic medical devices remain in an individual undergoing treatment. For example, coronary and peripheral procedures involve the insertion of diagnostic catheters, guide wires, guide catheters, PTCA balloon catheters (for percutaneous transluminal coronary angioplasty) and stents in blood vessels. In-dwelling sheaths (venous and arterial), intraaortic balloon pump catheters, tubes in heart lung machines, GORE-TEX surgical prosthetic conduits and in-dwelling urethral catheters are other examples. There are, however, complications which can arise from these medical procedures. For example, the insertion of synthetic materials into lumen can cause scaring and restenosis, which can result in occlusion or blockage of the lumen. Synthetic materials in the blood vessels can also cause platelet aggregation, resulting in some instances, in potentially life-threatening thrombus formation.
Nitric oxide (referred to herein as xe2x80x9cNOxe2x80x9d) inhibits the aggregation of platelets. NO also reduces smooth muscle proliferation, which is known to reduce restenosis. Consequently, NO can be used to prevent and/or treat the complications such as restenosis and thrombus formation when delivered to treatment sites inside an individual that have come in contact with synthetic medical devices. In addition, NO is anti-inflammatory, which would be of value for in-dwelling urethral or TPN catheters.
There are, however, many shortcomings associated with present methods of delivering NO to treatment sites. NO itself is too reactive to be used without some means of stabilizing the molecule until it reaches the treatment site. NO can be delivered to treatment sites in an individual by means of polymers and small molecules which release NO. However, these polymers and small molecules typically release NO rapidly. As a result, they have short shelf lives and rapidly lose their ability to deliver NO under physiological conditions. For example, the lifetime of S-nitroso-D,L-penicillamine and S-nitrosocysteine in physiological solution is no more than about an hour. As a result of the rapid rate of NO release by these compositions, it is difficult to deliver sufficient quantities of NO to a treatment site for extended periods of time or to control the amount of NO delivered.
Polymers containing groups capable of delivering NO, for example polymers containing diazeniumdiolate groups (NONOate groups), have been used to coat medical devices. However, decomposition products of NONOates under oxygenated conditions can include nitrosamines (Ragsdale et al., Inorg. Chem. 4:420 (1965), some of which may be carcinogenic. In addition, NONOates generally release NO, which is rapidly consumed by hemoglobin and can be toxic in individuals with arteriosclerosis. Further, the elasticity of known NO-delivering polymers is generally inadequate, making it difficult to coat medical devices with the polymer and deliver NO with the coated device under physiological conditions. Protein based polymers have a high solubility in blood, which results in short lifetimes. Finally, many NO-delivering polymers cannot be sterilized without loss of NO from the polymer and amounts of NO delivered are limiting.
There is, therefore, a need for new compositions capable of delivering NO to treatment sites in a manner which overcomes the aforementioned shortcomings.
The present invention is directed to novel polymers with xe2x80x94SNO groups, also referred to as S-nitrosyl groups. Polymers with xe2x80x94SNO groups are referred to as xe2x80x9cS-nitrosylated polymersxe2x80x9d. The polymers of the present invention generally have at least one xe2x80x94SNO group per 1200 atomic mass units (amu) of the polymer, preferably per 600 amu of the polymer.
In one embodiment, the S-nitrosylated polymer has stabilized -S-nitrosyl groups. The polymer generally comprises at least one stabilized S-nitrosyl group per 1200 amu, and often one stabilized S-nitrosyl group per 600 amu. An S-nitrosyl group can be stabilized by a free thiol or a free alcohol from the same molecule. Each stabilized xe2x80x94SNO group is stabilized by a different free alcohol or thiol group. Thus, a polymer with a stabilized S-nitrosyl group generally has at least one free alcohol and/or thiol group per 1200 amu of polymer, preferably per 600 amu of polymer. Another embodiment of the present invention is an S-nitrosylated polymer prepared by polymerizing a compound represented by Structural Formula (I): 
R is an organic radical.
Each Xxe2x80x2 is an independently chosen aliphatic group or substituted aliphatic group. Preferably, each Xxe2x80x2 is the same and is a C2-C6 alkylene group, more preferablyxe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2xe2x80x94.
p and m are independently a positive integer such that p+m is greater than two. Preferably, p+m is less than or equal to about 8.
Another embodiment of the present invention is a method of preparing an S-nitrosylated polymer with stabilized -S-nitrosyl groups. The method comprises polymerizing a compound represented by Structural Formula (I).
In another embodiment of the present invention, the S-nitrosylated polymer is an S-nitrosylated polythiolated polysaccharide. Preferably, the polythiolated polysaccharide is a polythiolated cyclodextrin.
Another embodiment of the present invention is an S-nitrosylated polymer prepared by reacting a polythiolated polymer with a nitrosylating agent under conditions suitable for nitrosylating thiol groups. Preferably, the polythiolated polymer is a polythiolated polysaccharide.
Another embodiment of the present invention is a method of preparing an S-nitrosylated polymer. The method comprises reacting a polymer having a multiplicity of pendant thiol groups, i.e., a polythiolated polymer, with a nitrosylating agent under conditions suitable for nitrosylating free thiol groups. In a preferred embodiment, the polythiolated polymer is a polythiolated polysaccharide.
Another embodiment of the present invention is an article which is capable of releasing NO. The article is coated with at least one of the polymers of the present invention. The article can be any device for which a useful result can be achieved by NO release, including a medical device suitable for implantation at a treatment site in a subject (individual or animal). The medical device can then deliver nitric oxide to the treatment site in the subject. In another example, the article is a tube or catheter for contacting a bodily fluid of a subject.
Another embodiment of the present invention is a method of delivering nitric oxide to a treatment site in an individual or animal. The method comprises providing a medical device coated with an S-nitrosylated polymer of the present invention. The medical device is then implanted into the individual or animal at the treatment site. Nitric oxide can be delivered to a bodily fluid, for example blood, by contacting the bodily fluid with a tube or catheter coated with one or more of the polymers of the present invention.
Yet another embodiment of the present invention is a method of preparing an article capable of releasing NO, e.g., a medical device for delivering nitric oxide to a treatment site in an individual or animal or a tube or catheter for contacting a bodily fluid. The method comprises coating the article with an S-nitrosylated polymer of the present invention.
Polymers with stabilized S-nitrosyl groups and polymers obtained by polymerizing compounds represented by Structural Formula (I) can cause vasodilation in bioassays (Example 16). These polymers have also been found to deliver NO for extended periods of time lasting at least several weeks (Example 15). Thus, they are expected to be useful as coatings on medical devices for implantation in subjects, thereby delivering NO at treatment sites.
Medical devices coated with S-nitrosylated polythiolated polysaccharides are effective in reducing platelet deposition and restenosis when implanted into animal models. Specifically, stents coated with an S-nitrosylated xcex2-cyclodextrin or an S-nitrosylated xcex2-cyclodextrin complexed with S-nitroso-N-acetyl-D,L-penicillamine or S-nitroso-penicillamine resulted in decreased platelet deposition when inserted into the coronary or cortoid arteries of dogs compared with stents which lacked the polymer coating (Example 12). It has also been found that S-nitrosylated xcex2-cyclodextrin and S-nitrosylated xcex2-cyclodextrin complexed with S-nitroso-N-acetyl-D,L-penicillamine cause vasodilation in bioassays (Examples 8 and 10). Furthermore, the disclosed S-nitrosylated polysaccharides have been found to deliver NO-related activity for extended periods of time and to exhibit increased shelf stability compared with compounds presently used to deliver NO in vivo.
A further advantage of the S-nitrosylated polysaccharides is that they lack the brittleness of other NO-delivering compositions and have sufficient elasticity to coat and adhere under physiological conditions to medical devices such as stents.